Population-based analysis of ocular Chlamydia trachomatis in trachoma-endemic West African communities identifies genomic markers of disease severity

A R Last,J Hadfield,T G Clark,C H Roberts,M Nabicassa,J Phelan,H Pickering,M J Holland,I N Clarke,N R Thomson,S E Burr,E Cassama,R L Bailey,H M B Seth-Smith,D C W Mabey,L T Cutcliffe,F Coll

doi:10.1186/s13073-018-0521-x

Abstract

BackgroundChlamydia trachomatis (Ct) is the most common infectious cause of blindness and bacterial sexually transmitted infection worldwide. Ct strain-specific differences in clinical trachoma suggest that genetic polymorphisms in Ct may contribute to the observed variability in severity of clinical disease.MethodsUsing Ct whole genome sequences obtained directly from conjunctival swabs, we studied Ct genomic diversity and associations between Ct genetic polymorphisms with ocular localization and disease severity in a treatment-naïve trachoma-endemic population in Guinea-Bissau, West Africa.ResultsAll Ct sequences fall within the T2 ocular clade phylogenetically. This is consistent with the presence of the characteristic deletion in trpA resulting in a truncated non-functional protein and the ocular tyrosine repeat regions present in tarP associated with ocular tissue localization. We have identified 21 Ct non-synonymous single nucleotide polymorphisms (SNPs) associated with ocular localization, including SNPs within pmpD (odds ratio, OR = 4.07, p* = 0.001) and tarP (OR = 0.34, p* = 0.009). Eight synonymous SNPs associated with disease severity were found in yjfH (rlmB) (OR = 0.13, p* = 0.037), CTA0273 (OR = 0.12, p* = 0.027), trmD (OR = 0.12, p* = 0.032), CTA0744 (OR = 0.12, p* = 0.041), glgA (OR = 0.10, p* = 0.026), alaS (OR = 0.10, p* = 0.032), pmpE (OR = 0.08, p* = 0.001) and the intergenic region CTA0744–CTA0745 (OR = 0.13, p* = 0.043).ConclusionsThis study demonstrates the extent of genomic diversity within a naturally circulating population of ocular Ct and is the first to describe novel genomic associations with disease severity. These findings direct investigation of host-pathogen interactions that may be important in ocular Ct pathogenesis and disease transmission.

Highlights

Chlamydia trachomatis (Ct) is the most common infectious cause of blindness and bacterial sexually transmitted infection worldwide
Conjunctival swabs collected during a cross-sectional population-based trachoma survey on the Bijagós Archipelago yielded 220 ocular Ct infections detected by Ct plasmid-based droplet digital polymerase chain reaction (ddPCR)
Of the ten single nucleotide polymorphism (SNP) initially identified within the Ct plasmid sequences, none fulfilled the quality filtering criteria, and they were not retained for the genome-wide association analyses

Summary

Introduction

Chlamydia trachomatis (Ct) is the most common infectious cause of blindness and bacterial sexually transmitted infection worldwide. Ct strain-specific differences in clinical trachoma suggest that genetic polymorphisms in Ct may contribute to the observed variability in severity of clinical disease. The obligate intracellular bacterium Chlamydia trachomatis (Ct) is the leading infectious cause of blindness (trachoma) and the most common sexually transmitted bacterial infection [1, 2]. Serovars largely differentiate biological groups associated with trachoma (A–C), sexually transmitted disease (D–K) and lymphogranuloma venereum (LGV) (L1–L3). Ct strains share near complete genomic synteny and gene content [4], suggesting that minor genetic changes influence pathogen-host and tissue-specific infection characteristics [5,6,7,8]. There are only 31 published ocular Ct genome sequences [4, 9,10,11,12]

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